Video Treatment Decisions for NTM-PD: An International Guideline-Based Approach to Optimizing Outcomes in MAC Lung Disease Play Pause Volume Quality 1080P 720P 576P Fullscreen Captions Transcript Chapters Slides Treatment Decisions for NTM-PD: An International Guideline-Based Approach to Optimizing Outcomes in MAC Lung Disease Overview I'm Patrick Flume. I'm at the Medical University of South Carolina in Charleston, and I'll be discussing some treatment decisions for non tuberculosis mycobacterium pulmonary disease, using the recent recently updated guidelines to define the approach to care. This is one of five programs based on these treatment decisions, and I invite you to look at the other sites as well to see other perspectives. This is a CMI and CE certified webinar is provided by the University of Massachusetts Medical School and CMI Education. Resource is it is supported by an unrestricted independent educational grant from enzman and to receive CMI credit, just click the CMI link below this video to access the online evaluation form. I want to start by just giving a brief update on the increasing prevalence of NTM pulmonary disease and as kinesis een in this graph, when you look at Michael bacterial cultures, whereas we've seen tuberculosis cultures decreasing over time, the number of cultures that we're finding with non tuberculosis mycobacterium has been increasing. And if you look over the decade between 1997 and 2007, that represents about an 8.2% increase per year. There's been a lot of conjecture as to why we're seeing Mawr cases of NTM pulmonary disease. A big part of it might be that there is a greater awareness and people are looking for it in patients. There is also concerned that that there are greater numbers at risk for developing NTM pulmonary disease, and it doesn't really matter is just that we are recognizing an increasing number of cases. I mentioned that there have recently been updated guidelines for the diagnosis and management of NTM pulmonary disease, and as you can see, the original guidelines were published back in 2007 and it was updated most recently in 2020. What is difference is that there is greater collaboration among the societies relevant to, uh, treatment of patients with NTM pulmonary disease. So as before, it was with the American Throttle Society and the Infectious Diseases Society of America. Now there is inclusion of a more global enterprise approach to developing recommendations. Key to these recommendations are the guidelines related to the diagnosis of NTM pulmonary disease. What are we actually talking about it and there are three critical areas of interest. One is that the subject has clinical symptoms that air suggestive of an NTM infection. These may include pulmonary symptoms. Typically, that would be cough, possibly with sputum production. Maybe even him opt Icis. But there also may be systemic symptoms that include fevers. It might be low grade sweats occurring at night sometimes but usually soaking their shirt type of sweats. Fatigue is a very big symptom in these patients. Loss of appetite, which may then result in weight loss. As you can see these air pretty non specific symptoms and so may represent a number of different diagnoses. Then we look for radiologic features of NTM infection. These may present as na jewels. They might be in the presence of bronchi. ECT assists. And there is debate about whether they contribute to the development of bronchi actresses or are a consequence of bronchi actresses. And then some will go on to develop actual cavities. Thes cavities can be small. They could be quite large on thick walled making, creating clearly evidence of destructive lung disease. And then, of course, you have to have evidence of the bug. You have to have cultures that demonstrate the presence of the organism. Three guidelines recommend that you may obtain this through a bronchoscopy. And so if you do a wash or lavage through a bronchoscopes and you find NTM present in there, that usually is sufficient to know that that bug is actually presence in the lower airways sputum cultures. The guidelines recommend at least two positive sputum cultures, and the reason for this is there is the potential for there to be transient presence of the organism in the mouth. And so one positive culture may not really represent evidence of lower airways infection and then finally, lung biopsy with histological features of granuloma tha and also positive for culture. But a key caveat to making the diagnosis is that you have excluded other diagnoses that may account for these clinical or radiographic symptoms features. So, for example, the patient with cystic fibrosis who has bronchi actresses and chronic airways infection with other pathogens like Pseudomonas or staff is Are there symptoms that they have a result of their bronchi actresses and other infection, or is in fact due to the mycobacterium that was identified in those cultures. So the onus is upon us to demonstrate that it is in fact, the mycobacterium, which is causing the problems that would warrant therapy. So, in some cases, making the diagnosis is not as difficult. Eso in this particular case I have a patient who has occasional symptoms has an occasional cough, maybe a little bit of sputum production, but really no systemic symptoms at all. There's no fevers, no sweats, the way to stable. You can see on the X ray. There are just a few nah jewels that air present that were picked up when the study was done for other purposes, but not an extensive amount of disease. And then there were multiple speed, um, samples, only one of which grew Mac. All the smears were negative. So this is a subject that perhaps doesn't actually have Mac pulmonary disease. In contrast, is this subject who has daily symptoms? These coughing spells, arm or spasmodic on prolonged, and they're producing sputum. Along with that cough, there are, in fact, systemic symptoms with intermittent fevers, night sweats, overwhelming sense of fatigue, Onda also experiencing weight loss. They've kind of hit the trifecta of symptoms, and the radiographic features air pretty obvious where you're seeing, not merely just bronchial. Catic changes Cava Terry disease with extensive consolidation out of budding that pleural membrane. And in this person, repeated sputum samples are positive for Mac growing mycobacterium avian complex. But the smears are also paused of suggesting a greater burden of infection. I don't think anyone is gonna have any problem arguing that this patient would benefit from treatment for their Mac pulmonary disease. So let's start with a more difficult case. And in this case, this woman is 56 years old. 10 years prior, she had flu like symptoms. Chest X ray was done, which was normal, but the CT scan was interpreted as having mild bronchi actresses. She underwent bronchoscopy at that time, and the culture came back growing, Mac. But the smear had been negative. She was not treated for the Mac. 10 years later, she is referred because she has this non productive cough. In fact, it's more really that she's clearing her throat with great frequency. There's no fever, no night sweats, the weight loss not breathless on exam. She has some crackles heard interior Lee. Her oxygenation is normal. Her CT scan reveals evidence of mild bronchi actresses. So structurally you can see the airways air enlarged bilaterally. And there are Nagy. Alors, findings principally in the right middle lobe but also in the lower lobes that are compatible with a diagnosis of Michael Bacterial lung disease. Students were obtained, Um, on three occasions, and they grew methicillin susceptible staph aureus. The smears were all negative for acid fast bacilli. I'm but the cultures grew mad. So now the question is, does she meet your criteria for Mac pulmonary disease? Well, she clearly has cough got radiographic features that are compatible with that, and she meets the criteria of a least two sputum cultures. Positive for Mac. But the question here is, Are there any other potential explanations? And we excluded other possible diagnoses. So additional testing that was done in her case was a *** level that was normal. She had no antibodies against aspirin. Gillis. She did not have immune deficiency with a normal IGC. She was tested for CF with a sweat chloride, which also was interpreted as normal. She was started on airway clearance therapies, but she was also had described symptoms that were suggestive of gastroesophageal reflux disease. And so it was put on both conservative coverage measures to try and prevent esophageal reflux and acid suppression. What happened was she got better. Her cough improved. She had Mawr energy. She felt like she could do a lot more and she actually gained weight. So the question now is, does she meet the criteria for Mac pulmonary disease? What the guidelines would tell you is that well, she does. She meets the criteria for NTM lung disease in terms of having symptoms in terms of having radiographic features and obviously the micro biologic features. But the symptoms got better. And so if we're now talking about a person who symptoms have resolved while they say we suggest initiation of treatment rather than watchful waiting, especially in the context of positive F sputum smears in or kava terry lung disease, she didn't have positive smears. She does not have cava terry lung disease. And so the recommendation is that the decision to treat should be individualized that you're trying to evaluate. What am I trying to make better? What are the benefits of therapy and what are the risks associated with that therapy? So the reasons to treat someone who has Mac pulmonary disease is whether you believe the symptoms or the radiographic features they have are indeed the result of Mac infection, or that with time, things are going to get worse. And if we knew that to be the case, well, then certainly treating earlier would be advised. But we don't have any testing that can tell us who is likely to develop progressive disease. So in the case, if one elected toe not treat for Mac, which is what we chose to do in this case, these patients should be monitored over time. So what we tell our patients is, even though I'm choosing to not recommend therapy today, we reserve the right to change our mind because there may be features that make it very clear to us now that in fact the Mac is the culprit and we would recommend therapy. So if the targets of therapy are symptomatic improvement, microbiological cure and then possibly even radiographic improvement, you need to know, what is it that you're actually trying to make better. So if a person has no symptoms and I'm going after microbiological cure, did I really helped them in the long run? If I don't have any knowledge of whether that is going to develop progressive infection, if clearly our goal is symptomatic improvement. We need to define what symptoms we intend to improve. In this first case, she actually had cough. They got better with other measures. So how can I do better than that? Radiographic improvement. These? Nah, Jules may come and they go, Uh, if they're if they're disappearing is possible because of treatment of the infection. It also might be That is because that you've successfully prevented them from the recurrent aspiration causing these new nah jewels to occur. Bronchi excesses is not likely to improve with therapy cavities might. They might get smaller, might get thin walled. So there are some features that might improve. But we advise our patients That's not our primary goal. Our primary goal is trying to achieve cure on improvement in their symptoms. So that takes us to our second case. This woman is 66 years old. She was referred with this history of recurrent diagnosis of pneumonia over the last 10 years. She would have intermittent symptoms. They weren't coughing every day, but she would have these symptoms. These exacerbations of these symptoms leading to treat with antibiotics with the diagnosis of pneumonia. But in truth, it really wasn't better and someone really shouldn't have pneumonia that often she presents to the clinic with this history of intimate recent history of intermittent cough, small amount of speed and production. Know who mocked Assis. She denies any fever. There are no night sweats. What she reports is extreme fatigue. Wait has been stable, but she's actually quite thin with a body mass index of 17. Think when you look at her CT scan, there is no doubt that she has features of disease, that she's got bronchi actresses bilaterally. She has peripheral modules on this particular cut, and then from a micro biologics standpoint, she had undergone a bronchoscopy a couple of years before that was smear negative and grew Mac Subsequent cultures you can see done in March and the November and December of 2018 did not grow any other bacteria just usual or a floor. Um, the smear was repeatedly negative, but it looks like it's now positive for Mac. In the subsequent two cultures, additional data were obtained her i G e and was in the normal range. There were no antibodies against aspirin. Gillis to suggest a B p a. Her I G was normal some studies done looking for autoimmune disease were also normal. Sweat chloride was actually a little bit higher than you'd expect at 46 million moles was repeated with still a little bit high in that indeterminant range. But testing for cystic fibrosis looking at gene mutations did not identify any of the more common CFTR gene mutations. So in this case she meets the criteria of cough and fatigue. She meets the radiographic features of modules and bronchi actresses. She has microbiological features with the positive sputum cultures, and we've done due diligence to try toe, exclude other diagnoses. If we now are deciding to treat for Mac pulmonary disease, the guidelines recommend a three drug regimen that's inclusive of a macro lied. The reason for that is because Mac relied susceptibility is the most consistent predictor of treatment. Success. Preference of a three drug regimen over a two drug regimen was based upon a lack of data to know whether having three drugs is better than two drugs at preventing the selection for resistance to, um, Acrolein. So although we have an ongoing study comparing a to drug to a three drug regimen, the discomfort I think of the committee was just they'd rather have mawr than less until we have data to suggest that that it's safe and effective. There are also debates about whether a daily regimen of therapy or can you get by with a three times a week regimen of therapy Eyes justus Good. Obviously, that would reduce the potential burden of treatment. And the guidelines recommend a three times weekly regimen that is acceptable for treatment of pulmonary Mac when there is nodule or bronchi. Actresses. Setting of cava terry disease requires, um, or aggressive antibiotic regimen, so our patient was instructed in effective means of airway clearance. This included nebulizer, hyper tonic sailing and oscillating positive exploratory pressure device. She was treated empirically for gastroesophageal reflux, but between these two measures, there was not clear evidence of improvement in her symptoms. And so she was initiated on a three drug regimen, including a zip through Mayes and death and bottle and rib champion three times a week, targeting her Mac. The organism was, in fact, susceptible to the macro lights. When we choose medications, we have to be cognizant that these medications can cause problems. All medications come with baggage. Some of these features are really just an intolerable ity. And what you see with this list of medications that nausea is a frequent occurrence with these therapies. It's a reason that we don't introduce all three drugs simultaneously, but we'll bring them on individually and bring the other 2nd and 3rd drug on pretty quickly to try and reduce the risk of untoward nausea. And then, of course, um, aversion to want to take these medications again. Uh, there should be a plan for monitoring for other complications associated with these drugs. So, for example, with the family tall doing periodic ophthalmic evaluations because of the risk of optic. Nor itis, uh, making sure that with the right champions that there's no risk associated with liver disease, getting EKGs looking for QTC prolongation, and then a careful review of their and other medications because of the potential for drug drug interactions. In particular, rifampin doesn't play well with many of the other medications, So therapy was started in this case in January of 2019, and what you can see are the subsequent cultures. So we initially have started in March of 2018, when the culture was negative But October November in that year were both positive. We wouldn't expect the January culture to be different since she was started on therapy. Then you can see February also was positive for Mac. But subsequent cultures in March, April and May were all negative. This is what we mean when we talk about the term culture conversion. Now, three subsequent cultures and um that are negative is a research definition for cultural conversion might be more rigorous than what is needed in the clinical setting. But if we are looking to try and achieve microbiological cure, there should be some assessment of subsequent sputum cultures to assess the response to therapy. If a person goes from producing sputum to no longer producing sputum, perhaps that meets the definition of a negative culture. This method becomes more complicated in those patients who do not produce sputum, and the definite diagnosis was made by bronchoscopy cause we're not recommending that we do bronchoscopy every month, but what we try to achieve is this goal of culture conversion and then in terms of the duration of therapy. The guidelines recommend treatment for 12 months after culture conversion, so in that particular setting the first negative culture was in March of that of 2019. Because the second cultures continued to be negative, we would have advised that patient that we would plan to treat until March of 2020 at which time we would stop therapy. Let's take on another case 67 year old female who's had this longstanding diagnosis of bronchi actresses and, in fact, had a history of home opt ASUs early on and was treated with a right middle lobe lobe ectomy. Uh, because she continued to have problems related to him. Optimizes cultures had grown aspirin, Gillis and she had been treated with a tree. Khanna's all but there was no evidence of benefit in terms of symptom relief, so she was referred to the clinic because of these recurrent bouts of him. Opt Icis. Currently, she has a daily cough is productive, productive of a greenish student. There's no fever or night sweats, however. She does have weight loss and extreme fatigue. Her image ing shows diffuse bronchi, actresses, nodule or disease. There's some areas where that bronchi axis is quite large, starting to look as if these cavities air forming it is throughout the lung. Sputum cultures repeatedly were positive for Mac, but the smears were also positive. You can see through 2017 the subsequent cultures that had been positive. So she clearly meets these criteria of coffin home opt, ASUs fatigue and weight loss. She has radiographic features with the diagnosis and she clearly meets the micro biologic. Um, we did exclude other diagnoses. She too is instructed in airway clearance therapies and treated empirically for reflux. Um, but we started in tm antibiotic therapy, including Is it through Mayes and Death and be tall and right champion. And in this case, you see that we started with daily therapy. The reason for that was because the extent of disease and the occurrence of home opt Assis Um so she was started on therapy in November of 2017. You see the previous sputum cultures in January, May in October that I've shown you previously so subsequent cultures In December, the smear had become negative. That might give a person confidence that there is some effect, even though the culture was still positive for Mac but subsequent cultures in January March in Maine again all smear positive, all growing back. So while on therapy, this is now six months into therapy, we clearly have not seen any change in the microbiological effect. Now one might ask if I have success in treatment of symptoms. Is that okay if I don't eradicate? On the other hand, if symptoms air persistent, you're not finding success with that. There must be a time in which we pivot in which we start thinking of making a change in the regiment because we're not achieving success as defined by culture conversion. Now, success with culture conversion does associate with underlying disease. So certainly with macro lights acceptability, as I had mentioned earlier resistant pathogens tend not to be very successful in terms of being able to get rid of the pathogen on Leah 5 to 15% success rate in clearance of the um achieving culture conversion. Similarly, we have greater chance of success in those patients who have nodule or bronchi actresses. Compared to those who have cava terry disease that with kava terry disease, we see less than a 50% success rate for Mac pulmonary disease. So from the get go, there can be greater problems. And that's why the guidelines even suggest the potential of adding intravenous amicus in 1/4 agent in the treatment of patients who have cava terry lung disease. So there are some considerations when you don't achieve culture conversion. One of those might be to repeat your susceptibility testing to see if we're using drugs in which the bug is resistant to checking serum drug levels to assure that they're properly absorbing the medication and getting to drug levels that we think are more likely associated with success. This is a controversial issue, but there are some centers that do, in fact, monitor serum drug levels and then, um, the issue of, um, changing your therapy. And there are many options that one might consider that might be driven by the susceptibility testing. But we tend to think of these as whether it's better to, um, um, give systemic therapy, meaning, um either Orel agents or intravenous agents or topical therapy where we heiress allies the drug and get it into the lungs. So systemic therapy options might include intravenous Amma, Cason and, as I mentioned, that is recommended for subjects with kava terry disease or using off label Cliff Azemi, which is only able to obtain through a special program initiated by the FDA. The other choice is using topical therapy and am a case in liposomes inhalation Suspension, or Alice is an option that has been granted approval by the FDA for use in patients with refractory to treatment disease. So the approach we took was, we reinforce the airway clearance therapies again. We're using nebulizer, hyper tonic sailing and oscillating pep. She's remained on therapy for reflux. We did susceptibility testing. The bud was susceptible to macro lights and Munich like asides. And so what we changed chose to do with her antibiotic regimen was to continue the three drug Orel regimen with the addition of the inhaled life. A simple am, a case and solution, a za daily regimen. So we made those changes in July of 2018. As you can see in July, that smear had been two plus again growing Mac. By August, the smear was negative, even though it was still growing back. And then in September, we had achieved culture conversion because cultures were in subsequent November in January had achieved negative cultures and our goal for therapy within to treat until the following September of 2000 and 19. Let's try one other different case. Uh, this is a 69 year old female, and she had previously been treated for Mac pulmonary disease. She never achieved culture conversion. She had been on multiple different antibiotics, which included Macro Lives, a family tall right Fam pond, Cliff Azemi and Inhaled AM A case. And and all this was complicated by some hearing loss. She comes to the clinic with a daily, non productive cough. There's no fever, but she has frequent night sweats. There's no weight loss. Sputum cultures in May of 2019 had been positive on smear and culture, and susceptibility testing had demonstrated a resistance to the macro lights you can see in subsequent cultures. In December, March in September, all were positive for Mac and two or smear positive. On her CT scan, she has this dense consolidation. It's not clear if there's a cavity that's just filled or whether it is just a large nodule or density. There is evidence of bronchi, actresses and na jewels and other parts of the lung, but this was the more focal compartment associated with disease, So the guidelines, um, in terms of addressing a surgical option. Could we remove this much like we're removing a cancer? Would that be of benefit to these patients? And so their recommendation is that in selected patients that surgical resection as an edge of into medical therapy, um, could be done, and the indications were failure of medical management. So despite antibiotics, the infection persists. Have it? Terry? Disease is very difficult to eradicate on because and clear infection in that drug resistant isolates. And also, if there are complications such as recurrent home opt ASUs or even massive Tomatis is that you're worried that she would not built to sustain that airway. But these air selected patients and expert consultation, ideally with surgeons who have considerable experience with surgical resection of Michael bacterial infection. So is surgery an option? I've already given you the indications for surgery, but there are other key factors that led to the patient. Primarily, this is for localized disease. That does not mean they can't have evidence of micro bacteria and other parts of the lung, because there is very likely that will be nodule that are present elsewhere, maybe even mild bronchi actresses. But there is focal disease that could be removed. And obviously, then the patient must be able to tolerate a reception. We did refer this patient as a potential candidate for surgery. They deemed her a good candidate for surgery, and she went removal of her right upper low. There was some immediate post operative challenges because of Tor Shin of the Airways, and this was only rectified by removal of the right middle lobe. A bronchoscopy done at the time of that second procedure. Leveraging the right lower lobe did not find any AFB present. And so she healed well from the surgery, and we continued antibiotic therapy with a goal towards completion of the planned course of therapy. So I will conclude, then, by just refreshing your memory that NTM palmeri disease is a condition with it is increasingly prevalent. Uh, we are finding this in many of our patients. Um, and I expect we will continue to find many patients infected with Michael bacteria. We do have guidelines for the diagnosis and treatment of NTM pulmonary disease. These have been recently updated and provide a resource for clinicians when they're trying to make treatment decisions and treatment. Considerations should include knowing how to identify and treat underlying or associated factors. This is where treatment of reflux and airway clearance treatment of underlying causes are of critical importance. Know why you are treating or not, um, so that you can have a plan for to engage your success or if you're choosing not to treat To monitor thio, make sure there is no evidence of progression of disease and then monitor closely for tolerable ity, toxicity and response to therapy. So with that, I will close and thank you for your attention and please click on the site to obtain your CMI associated with this program. Thank you. Published February 3, 2021 Created by
